Nam Jae Hyun, Kim So-Yeon, Seong Hasoo
Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-Gu, Deajeon, 34114, Republic of Korea.
Nanoscale Res Lett. 2018 Apr 13;13(1):101. doi: 10.1186/s11671-018-2519-0.
Synergistic effects of multiple drugs with different modes of action are utilized for combinatorial chemotherapy of intractable cancers. Translation of in vitro synergistic effects into the clinic can be realized using an efficient delivery system of the drugs. Despite a few studies on nano-sized liposomes containing erlotinib (ERL) and doxorubicin (DOX) in a single liposome vesicle, reliable and reproducible preparation methods as well as physicochemical characteristics of a non-PEGylated nanoliposome co-encapsulated with ERL and DOX have not been yet elucidated. In this study, ERL-encapsulated nanoliposomes were prepared using the lipid film-hydration method. By ultrasonication using a probe sonicator, the liposome diameter was reduced to less than 200 nm. DOX was loaded into the ERL-encapsulated nanoliposomes using ammonium sulfate (AS)-gradient or pH-gradient method. Effects of DOX-loading conditions on encapsulation efficiency (EE) of the DOX were investigated to determine an efficient drug-loading method. In the EE of DOX, AS-gradient method was more effective than pH gradient. The dual drug-encapsulated nanoliposomes had more than 90% EE of DOX and 30% EE of ERL, respectively. Transmission electron microscopy and selected area electron diffraction analyses of the dual drug-encapsulated nanoliposomes verified the highly oriented DOX-sulfate crystals inside the liposome as well as the less oriented small crystals of ERL in the outermost region of the nanoliposome. The nanoliposomes were stable at different temperatures without an increase of the nanoliposome diameter. The dual drug-encapsulated nanoliposomes showed a time-differential release of ERL and DOX, implying proper sequential releases for their synergism. The preparation methods and the physicochemical characteristics of the dual drug delivery system contribute to the development of the optimal process and more advanced systems for translational researches.
具有不同作用模式的多种药物的协同效应被用于难治性癌症的联合化疗。利用高效的药物递送系统可将体外协同效应转化至临床应用。尽管有一些关于在单个脂质体囊泡中同时含有厄洛替尼（ERL）和阿霉素（DOX）的纳米级脂质体的研究，但尚未阐明非聚乙二醇化纳米脂质体与ERL和DOX共包封的可靠且可重复的制备方法以及理化特性。在本研究中，采用脂质膜水化法制备了包载ERL的纳米脂质体。通过使用探针超声仪进行超声处理，将脂质体直径减小至小于200 nm。采用硫酸铵（AS）梯度法或pH梯度法将DOX载入包载ERL的纳米脂质体中。研究了DOX载入条件对DOX包封率（EE）的影响，以确定一种有效的药物载入方法。在DOX的EE方面，AS梯度法比pH梯度法更有效。双药包封的纳米脂质体的DOX EE分别超过90%，ERL EE分别超过30%。对双药包封纳米脂质体的透射电子显微镜和选区电子衍射分析证实，脂质体内部DOX - 硫酸盐晶体高度取向，而纳米脂质体最外层区域的ERL小晶体取向较差。纳米脂质体在不同温度下均稳定，脂质体直径未增加。双药包封的纳米脂质体显示出ERL和DOX的时间差异释放，这意味着它们的协同作用有适当的顺序释放。双药递送系统的制备方法和理化特性有助于开发用于转化研究的最佳工艺和更先进的系统。
